Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.
Highlights
USING BIOMARKERS TOREVEAL THE EXTRA-MOTORUNDERPINNINGS OF AMYOTROPHICLATERAL SCLEROSISAmyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder defined by the neurodegeneration of motor neurons, while frontotemporal dementia (FTD) is the most common presentation of frontotemporal lobar degeneration (FTLD) and is characterized by progressive neurodegeneration of frontotemporal structures [1, 2]
Impairment in ALS Considerable progress has been made in unraveling the genetics of ALS and FTLD, and it is clear that the genetics of these two neurodegenerative conditions overlap significantly [55]
Genes such as TANK-binding kinase-1 (TBK1) [65,66,67,68,69], Sequestosome-1 or p62 (SQTSM1) [70], Optineurine protein (OPTN), and Valosin-containing protein (VCP) that are associated with FTD, inclusion body myositis, motor neuron disease, and Paget’s disease encode proteins related to protein degradation [71, 72]
Summary
USING BIOMARKERS TOREVEAL THE EXTRA-MOTORUNDERPINNINGS OF AMYOTROPHICLATERAL SCLEROSISAmyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder defined by the neurodegeneration of motor neurons, while frontotemporal dementia (FTD) is the most common presentation of frontotemporal lobar degeneration (FTLD) and is characterized by progressive neurodegeneration of frontotemporal structures [1, 2]. The diagnosis of ALS is based on the identification of motor signs and symptoms, while the diagnosis of FTD is based on cognitive, language, and behavioral features [3,4,5]. Recent evidence indicates that ALS can show varying degrees of cognitive and behavioral changes at diagnosis [6,7,8,9]. The exact mechanisms driving extra-motor neurodegeneration in ALS remain largely unknown. Filling this gap in our knowledge is essential to improve the diagnosis and management of patients with ALS and may impact end-of-life legal decisions [13, 14]
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